The Influence of GLP-1 on Glucose-Stimulated Insulin Secretion

Kjems, Lise; Holst, Jens J.; Vølund, Aage; Madsbad, Sten

doi:10.2337/diabetes.52.2.380

Cited by 538 publications

(385 citation statements)

References 36 publications

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“…In other words, with GLP-1 the subjects showed a completely normal insulin response to glucose. A similar observation (that GLP-1 can restore beta-cell responsiveness glucose in patients with Type 2 diabetes) was made by a study using an entirely different approach [79]. Moreover, the normal glucoseinduced inhibition of glucagon secretion was completely restored.…”

Section: Incretin Function In Diabetessupporting

confidence: 65%

“…Indeed, in 1993 one study could show that an iv infusion of GLP-1 could completely normalise plasma glucose concentrations, even in patients with advanced Type 2 diabetes [83]. As mentioned above, addition of GLP-1 might restore glucose-induced insulin secretion to normal values in the patients [77,79]. However, it should be noted that GLP-1 not only potentiates glucose induced insulin secretion, but also has numerous other effects, all of which seem to be desirable in the context of treating Type 2 diabetic patients (Table 1).…”

Section: Incretin Hormones As Therapeutic Agentsmentioning

confidence: 99%

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Incretins, insulin secretion and Type 2 diabetes mellitus

2004

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When glucose is taken orally, insulin secretion is stimulated much more than it is when glucose is infused intravenously so as to result in similar glucose concentrations. This effect, which is called the incretin effect and is estimated to be responsible for 50 to 70% of the insulin response to glucose, is caused mainly by the two intestinal insulin-stimulating hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Their contributions have been confirmed in mimicry experiments, in experiments with antagonists of their actions, and in experiments where the genes encoding their receptors have been deleted. In patients with Type 2 diabetes, the incretin effect is either greatly impaired or absent, and it is assumed that this could contribute to the inability of these patients to adjust their insulin secretion to their needs. In studies of the mechanism of the impaired incretin effect in Type 2 diabetic patients, it has been found that the secretion of GIP is generally normal, whereas the secretion of GLP-1 is reduced, presumably as a consequence of the diabetic state. It might be of even greater importance that the effect of GLP-1 is preserved whereas the effect of GIP is severely impaired. The impaired GIP effect seems to have a genetic background, but could be aggravated by the diabetic state. The preserved effect of GLP-1 has inspired attempts to treat Type 2 diabetes with GLP-1 or analogues thereof, and intravenous GLP-1 administration has been shown to be able to near-normalize both fasting and postprandial glycaemic concentrations in the patients, perhaps because the treatment compensates for both the impaired secretion of GLP-1 and the impaired action of GIP. Several GLP-1 analogues are currently in clinical development and the reported results are, so far, encouraging. The incretin effectThe incretin effect seems to play a major role in the regulation of glucose metabolism in healthy subjects. "The incretin effect" implies that ingestion of carbohydrates (glucose) causes the release from the intestinal mucosa of substances that enhance insulin secretion beyond the release caused by the absorbed glucose itself [1]. The effect can be quantified by comparing insulin or C-peptide responses to oral or intravenous glucose loads, adjusted to cause identical increases of plasma glucose concentrations. The much higher responses observed after oral administration

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Section: Incretin Function In Diabetessupporting

confidence: 65%

Section: Incretin Hormones As Therapeutic Agentsmentioning

confidence: 99%

Incretins, insulin secretion and Type 2 diabetes mellitus

2004

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“…10,11 Clinical studies have shown that diabetic individuals can exhibit decreased GLP-1 secretion, yet physiological responses to this incretin hormone remain largely intact. [12][13][14][15] As a result, therapeutic efficacy of GLP-1-receptor agonists has been demonstrated in individuals with type-2 diabetes. Beneficial effects of GLP-1 in the treatment of type-1 diabetes have also been recognized.…”

Section: Introductionmentioning

confidence: 99%

DsAAV8-mediated expression of glucagon-like peptide-1 in pancreatic beta-cells ameliorates streptozotocin-induced diabetes

et al. 2009

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Glucagon-like peptide-1 (GLP-1) is an incretin hormone that performs a wide array of well-characterized antidiabetic actions, including stimulation of glucose-dependent insulin secretion, upregulation of insulin gene expression and improvements in beta-cell survival. GLP-1-receptor agonists have been developed for treatment of diabetes; however, the short biological half-lives of these peptide-based therapeutics requires that frequent injections be administered to maintain sufficient circulating levels. Thus, novel methods of delivering GLP-1 remain an important avenue of active research. It has recently been demonstrated that self-complimentary, double-stranded, adeno-associated virus serotype-8 (DsAAV8) can efficiently transduce pancreatic beta-cells in vivo, resulting in long-term transgene expression. In this study, we engineered a DsAAV8 vector containing a GLP-1 transgene driven by the mouse insulin-II promoter (MIP). Biological activity of the GLP-1 produced from this transgene was assessed using a luciferase-based bioassay. DsAAV8-MIP-GLP-1 was delivered via intraperitoneal injection and beta-cell damage induced by multiple low dose streptozotocin (STZ) administration. Glucose tolerance was assessed following intraperitoneal glucose injections and beta-cell proliferation measured by PCNA expression. Expression of GLP-1 in Min6 beta-cells resulted in glucose-dependent secretion of biologically active GLP-1. Intraperitoneal delivery of DsAAV8-MIP-GLP-1 to mice led to localized GLP-1 expression in beta-cells and protection against development of diabetes induced by multiple low-dose STZ administration. This protection was associated with significant increase in beta-cell proliferation. Results from this study indicate that expression and secretion of GLP-1 from beta-cells in vivo via DsAAV8 represents a novel therapeutic strategy for treatment of diabetes.

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“…However, it is now accepted that there is no specific molecular defect of the GIP receptor in established diabetes, first-degree relatives or gestational diabetes [15][16][17]. Recognition that GLP-1 action is also impaired, to a lesser extent than GIP action, in type 2 diabetes [18], suggests that the diminished insulin response is linked to generalised beta cell secretory dysfunction, presumably stemming from beta cell glucose insensitivity [19].…”

Section: Introductionmentioning

confidence: 99%

Early administration of the glucose-dependent insulinotropic polypeptide receptor antagonist (Pro3)GIP prevents the development of diabetes and related metabolic abnormalities associated with genetically inherited obesity in ob/ob mice

et al. 2007

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Aims/hypothesis Ablation of gastric inhibitory polypeptide (GIP) receptor action is reported to protect against obesity and associated metabolic abnormalities. The aim of this study was to use prediabetic ob/ob mice to examine whether 60 days of chemical GIP receptor ablation with (Pro 3 )GIP is able to counter the development of genetic obesityrelated diabetes. Materials and methods Young (5-7 weeks) ob/ob mice received once daily i.p. injections of either saline vehicle or (Pro 3 )GIP (25 nmol kg −1 day −1 ) over a 60 day period. Food intake, body weight and circulating glucose and insulin were measured at frequent intervals. At 60 days, glucose tolerance, response to native GIP, postprandial responses, insulin sensitivity, HbA 1c , circulating hormones and plasma lipids were assessed. Results Body weight and food intake in (Pro 3 )GIP-treated mice did not differ from ob/ob controls. GIP receptor blockade significantly improved non-fasting glucose (p< 0.001), HbA 1c (p<0.05), glucose tolerance (p<0.001), meal tolerance (p<0.001) and insulin sensitivity (p<0.05). Remarkably, (Pro 3 )GIP treatment prevented the age-related development of diabetes, as none of these parameters differed significantly between treated ob/ob mice and normal age-matched lean controls. Circulating levels of glucagon, corticosterone, adiponectin and total cholesterol were unchanged by (Pro 3 )GIP, while levels of triacylglycerol, LDLcholesterol and resistin were decreased (p<0.05) compared with those in control ob/ob mice. Plasma and pancreatic insulin concentrations were generally lower after (Pro 3 )GIP treatment than in control ob/ob mice (p<0.01), but plasma insulin levels remained substantially raised (p<0.001) compared with those observed in lean controls. Conclusions/interpretation These data indicate that sustained GIP receptor antagonism provides an effective means of preventing the development of many of the metabolic abnormalities of obesity-driven diabetes.

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The Influence of GLP-1 on Glucose-Stimulated Insulin Secretion

Cited by 538 publications

References 36 publications

Incretins, insulin secretion and Type 2 diabetes mellitus

Incretins, insulin secretion and Type 2 diabetes mellitus

DsAAV8-mediated expression of glucagon-like peptide-1 in pancreatic beta-cells ameliorates streptozotocin-induced diabetes

Early administration of the glucose-dependent insulinotropic polypeptide receptor antagonist (Pro3)GIP prevents the development of diabetes and related metabolic abnormalities associated with genetically inherited obesity in ob/ob mice

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